Cardiac Myosin Inhibitors in Obstructive HCM: Mechanism, Regulatory Milestones, and Clinical Rationale

In this section, Dr Maron transitions to the emergence of cardiac myosin inhibitors as a novel therapeutic class, and Dr Masri details their mechanistic rationale. Mavacamten received US FDA approval in 2022 for symptomatic obstructive HCM, followed recently by the approval of aficamten. Both agents are indicated for patients with symptomatic obstructive disease, requiring demonstrable LVOT gradient at rest or with provocation. At present, their regulatory approvals are confined to obstructive HCM, with nonobstructive disease remaining an area of active investigation.

Masri explains that cardiac myosin inhibitors act directly at the sarcomere, reducing excessive actin–myosin cross-bridge formation and thereby attenuating pathologic hypercontractility. Although both drugs are negative inotropes by classification, their therapeutic aim is not to produce systolic dysfunction but to normalize an abnormally hyperdynamic ventricle. By modulating sarcomeric power generation, these agents decrease or eliminate mitral–septal contact, leading to marked reductions—or complete resolution—of the LVOT gradient and associated SAM-mediated mitral regurgitation.

Maron emphasizes that this sarcomere-targeted approach represents a paradigm shift compared with traditional negative inotropes, which rely on nonspecific hemodynamic effects rather than correction of the primary pathophysiologic mechanism. Phase 3 data with both mavacamten and aficamten demonstrate that profound gradient reduction translates into clinically meaningful gains in symptoms, functional class, and exercise capacity. The segment underscores that by addressing the root hypercontractile biology of HCM, cardiac myosin inhibitors have opened a “new era” in managing symptomatic obstructive disease.